Sina Rusta-Sallehy, BHSc1,2; Melinda Gooderham, MD, MSc, FRCPC3,4,5; Kim Papp, MD, PhD, FRCPC4,6

1McMaster University, Faculty of Health Sciences, Hamilton, ON, Canada
2University of Toronto, Faculty of Medicine, Toronto, ON, Canada
3Skin Centre for Dermatology, Peterborough, ON, Canada
4Probity Medical Research, Waterloo, ON Canada
5Queen’s University, Kingston, ON Canada
6K Papp Clinical Research, Waterloo, ON Canada

Conflict of interest:
MG and KP have been investigators, consultants, advisory board members and speakers for Amgen, Kyowa Kirin, Leo, MedImmune and Valeant.
KP has been a consultant for Astra Zeneca. SRS has no conflicts to disclose.

ABSTRACT
Interleukin (IL)-17 is important in the pathophysiology of psoriasis and has proven to be an effective therapeutic target. Brodalumab, the third commercially available IL-17 antagonist, was approved by the US FDA in February 2017 for the treatment of moderate-to severe plaque psoriasis. As brodalumab enters the marketplace, it is imperative to investigate its safety profile. We conducted a safety assessment of brodalumab using publicly available adverse event data from phase II and III clinical trials. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and candidiasis. The FDA issued a black box warning after six patients treated with brodalumab across four clinical trials committed suicide, but no causal relationship was identified. Current evidence suggests a similar safety profile for brodalumab compared to other IL-17 antagonists used to treat moderate-to-severe plaque psoriasis.

Key Words:
biologics, chronic plaque, psoriasis, IL-17, interleukin-17, interleukin-17A, monoclonal antibody, safety

Introduction

Interleukin (IL)-17 is important in the pathophysiology of psoriasis and has proven to be an effective therapeutic target. Brodalumab is an IL-17R inhibitor1 evaluated in rheumatoid arthritis2, Crohn’s disease3, and psoriatic arthritis4, and is approved for the treatment of moderate-to-severe, chronic plaque psoriasis in Japan, US, and Europe. Development in rheumatoid arthritis was stopped for futility.2 The Crohn’s disease program was terminated as a trend to worsening of disease was observed in a phase II study.3 Amgen terminated the psoriasis and psoriatic arthritis programs for commercial reasons,5 however, sufficient data had been collected for submission to regulatory agencies for approval. Brodalumab was approved by the Japanese Pharmaceuticals and Medical Devices Agency in July 2016 (Lumicef®), the US FDA in February 2017 (Siliq™), and the European Medicines Agency in July 2017 (Kyntheum®) for treatment of moderate-to-severe plaque psoriasis.

Given the mechanism of action, the anticipated safety profile of brodalumab should reflect that of other IL-17 blockers. More controversial is the posited reason for abandoning the psoriasis and psoriatic arthritis program. A numerical imbalance in the number of suicides occurring in patients receiving brodalumab compared to placebo was observed, which would affect the labelling requirements.6,7 Herein, we review the publicly available safety data for brodalumab across the entire development program.

Methods

To identify all available brodalumab randomized clinical trials (RCTs), a search of the ClinicalTrials.gov database was conducted with key words “brodalumab”, “KHK 4827”, OR “AMG 827”. Of the 30 studies retrieved, only those with available data that were completed or terminated early were included in the analysis. Studies with data unavailable, currently or not yet recruiting patients, or withdrawn studies were excluded. We also searched the PubMed database with the terms “brodalumab”, “KHK 4827”, OR “AMG 827”. After reviewing available studies, adverse event data was compiled from journal publications and appendices of 10 RCTs (six with open-label extensions) and one prospective case series (Table 1).

ClinicalTrials.gov Registry No.First AuthorPhaseDiseaseComparatorNDosing
NCT00975637Papp1IIPsoriasisPlacebo198Brodalumab 70 mg, 140 mg or 210 mg SC at week 0, week 1, then q 2 weeks or 280 mg SC at week 0 then q 4 weeks
NCT01748539Nakagawa8IIPsoriasisPlacebo151Brodalumab 70 mg, 140 mg or 210 mg SC at
week 0, week 1, then q 2 weeks
NCT01516957Mease4IIPsoriatic arthritisPlacebo168Brodalumab 140 mg or 280 mg SC at week 0,
week 1, then q 2 weeks
NCT01199289Busse9IIAsthmaPlacebo302Brodalumab 140 mg, 210 mg or 280 mg SC at
week 0, week 1, then q 2 weeks
NCT00950989Pavelka2IIRheumatoid arthritisPlacebo252Brodalumab 70 mg, 140 mg or 210 mg SC at
week 0, week 1, then q 2 weeks
NCT01150890Targan3IICrohn’s diseasePlacebo130Brodalumab 210 mg, 350 mg or 700 mg IV at
Day 1 and week 4
NCT01782937Yamasaki10IIPsoriatic erythroderma & generalized pustular psoriasisNone30Brodalumab 140 mg SC at week 0, week 1, then
q 2 weeks
NCT01708590 (AMAGINE-1)Papp11IIIPsoriasisPlacebo661Brodalumab 140 mg or 210 mg SC at week 0,
week 1, then q 2 weeks
NCT01708603 (AMAGINE-2)Lebwohl12IIIPsoriasisPlacebo Ustekinumab1831Brodalumab 140 mg or 210 mg SC at week 0,
week 1, then q 2 weeks
Ustekinumab 45 mg or 90 mg SC Day 1, week 4,
then q 12 weeks
NCT01708629
(AMAGINE-3)
Lebwohl12IIIPsoriasisPlacebo Ustekinumab1881Brodalumab 140 mg or 210 mg SC at week 0,
week 1, then q 2 weeks
Ustekinumab 45 mg or 90 mg SC Day 1, week 4,
then q 12 weeks
NCT02029495 (AMVISION-1)Not published13IIIPsoriatic arthritisPlacebo316Brodalumab 140 mg or 210 mg SC at week 0,
week 1, then q 2 weeks
Table 1: Phase II and III RCT data for brodalumab. SC = subcutaneous; IV = intravenous; q = every

Safety Assessment

As brodalumab has entered the marketplace, it is imperative to continually assess its safety. A safety assessment is an ongoing process evaluating events occurring in a specific population exposed to a medical compound compared to an appropriate general population. The highest quality data is acquired from adverse event reporting in placebo-controlled RCTs. These adverse events have standardized definitions of severity based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. To date, there have been six phase II and four phase III RCTs evaluating the efficacy and safety of brodalumab in treating psoriasis, psoriatic arthritis, Crohn’s disease, asthma and rheumatoid arthritis (Table 1).1-4,8-12 All studies had a 12-week induction period where patients received brodalumab on day 1, week 1, week 2, and subsequently every other week until week 10, and were assessed on week 12. Six of the studies continued with an open-label extension offering brodalumab to all patients. Adverse event data is currently available for open-label extensions until week 52, however, the phase II psoriasis study by Papp et al.14 has data available until week 120. A 52-week prospective case-series conducted by Yamasaki et al.10 investigating brodalumab’s efficacy in 30 patients with either generalized pustular psoriasis or psoriatic erythroderma was also included in our safety analysis. Targan et al.3 terminated their study prematurely as brodalumab was found to worsen Crohn’s disease activity. During the 12-week induction period within these studies, 4118 patients were treated with at least one dose of brodalumab. During the induction, the most common adverse events reported with brodalumab use were nasopharyngitis (7.4%), upper respiratory tract infection (5.6%), headaches (4.3%), arthralgias (3.0%), and injection site reaction (2.1%). Due to the immunosuppressive nature of brodalumab, serious infections, candidiasis, and neutropenia are considered adverse events of interest. Only 1.7% of brodalumab patients reported serious infections, similar to the placebo group (1.5%). Candidiasis was reported in 1.1% of patients, typically oropharyngeal, and 0.5% were found to have clinically insignificant neutropenia. Major adverse cardiovascular events, headache, fatigue, diarrhea, nausea, and vomiting were reported by less than 1% of participants. Targan et al.,3 similar to another IL-17 antagonist, secukinumab, discovered worsening of Crohn’s disease activity with IL-17 inhibition in 24 (18%) of 130 patients, and thus, this study was terminated early. Subsequent RCTs in other disease states excluded subjects with a history of Crohn’s disease.A total of 4340 patients received brodalumab for an extended duration of 52 to 120 weeks. The adverse event data was compiled from six open-label extensions and a 52-week study by Yamasaki and colleagues.10 The most common adverse events reported with longer duration of brodalumab therapy were injection site reaction (4.5%), Candida infections (4.1%), and nasopharyngitis (3%). Other side effects included upper respiratory tract infection (1.8%), serious infection (1.4%), arthralgias (1.1%), and neutropenia (1.1%). Headache, fatigue, major adverse cardiovascular events, and gastrointestinal adverse events (e.g., nausea, vomiting and diarrhea) were reported by less than 1% of patients. Depressed mood was described by only 1.5% of brodalumab patients, similar to the 1.3% of participants receiving ustekinumab during the AMAGINE-2 and AMAGINE-3 trials.12 All brodalumab clinical trials were stopped on May 22, 2015, as six participants treated with brodalumab, across all programs, committed suicide. Of these six, four were enrolled in psoriasis studies, one in the rheumatoid arthritis trial, and one in a psoriatic arthritis study.15 Of the four psoriasis patients, two completed suicide during the open-label extension of AMAGINE-2 and the remaining two occurred during the open-label extension of AMAGINE-1, one of which was deemed to be an unintentional heroin overdose on autopsy. One suicide was completed during the induction period of the rheumatoid arthritis study by Pavelka et al.2, and one during the AMVISION-1 open-label extension15. Our analysis showed that only 1.5% of patients who received brodalumab reported depressed mood. The FDA conducted a thorough analysis of the data available in 2015 and determined that there was no established drug-related risk of suicide or suicidal ideation.15 To date, there has been no additional data correlating brodalumab use and suicide.

Discussion

The spectrum of adverse events seen with brodalumab is consistent with other drugs blocking IL-17. Nasopharyngitis and upper respiratory tract infections were the most commonly reported infections. Candida infections, seen in 4% of patients, is consistent with other agents blocking IL-17.16,17 Though stopped for futility, patients in a study evaluating secukinumab for the treatment of Crohn’s disease showed a trend to worsening of disease compared to patients receiving placebo.18 The foregoing somewhat mirrors the results seen with brodalumab.3 Incidental and self-correcting neutropenia, seen with brodalumab, was also observed in programs with secukinumab and ixekizumab.16,17Suicidal ideation was reported at low rates across most clinical trial programs evaluating interventions for moderate-to-severe plaque psoriasis.7 The numerical imbalance of completed suicides seen in the brodalumab psoriasis studies warranted a boxed warning on the US FDA approved label, though the same label states there is no causal association between brodalumab exposure and suicide.19 Depression and suicidal ideation are common in the psoriasis population20, as they are in many chronic diseases21. Challenges in ascertaining differential rates in suicide include rates that vary of time22, rates that vary country to country23, and rates displaying significant differences in rates within the same country6.Overall, the safety profile of brodalumab is consistent with other drugs blocking IL-17 and broadly consistent with the spectrum of adverse events seen with biologic agents used to treat moderate-to-severe plaque psoriasis.

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